JPS61180766A - Manufacture of azetidinone intermediate - Google Patents

Abstract

Compounds of formula I <IMAGE> wherein R1 and R2 is each H, halo or an organic group, R3 is H or organic group, n=1 or 2, M is a heavy mono- or divalent metal, or M2A wherein M2 is a heavy divalent metal and A is an organic or inorganic group, are prepared by treating a starting penicillin in a solvent with a salt of M1 or M2A in the presence of a base at a temperature of from -70 DEG to 100 DEG C. The azetidinones of formula I are useful intermediates in the synthesis of beta -lactam antibiotics, esp.penem.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method for producing azetidinones, which are useful intermediates in the synthesis of β-lactam antibiotics, particularly Nemes. In particular, the present invention relates to a direct process for converting NaNam compounds of formula (II) below into heavy metal azetidinone mercaptides of formula (I) below.

(11) (I) In the formula, R1, R
2 is each independently hydrogen, halogen or an organic group,
R5 is hydrogen or an organic group, n is 1 or 2, M is a heavy metal M1 in the +'1 or +2 oxidation state, or a group M2A (where M2 is a heavy metal in the +2 oxidation state and A is organic or inorganic).

More particularly, when R1 and R2 are halogen, they are preferably bromo. R1 and R
When 2 is an organic group, it is preferably a substituted or unsubstituted C1-C4 alkyl group, more preferably a protected 1
-hydroxyethyl group, 01-C4 alkoxy group (e.g. methoxy group) or 2NR'R' (where R' and R1 together form a dicarboxylic acyl group or an organic ylidene residue or R' is a hydrogen atom or a trimethylsilyl group, sb and R' is an N-protecting group, e.g. , S or N functional group or C1-C8 alkyl or alkenyl substituted by halogen, cyanide, heterocycle, hydroxy, carboxy, aryl or cycloalkyl group, or R' is phenyl or heterocycle is a formula group).

When R3 is an organic group, it is e.g. methyl or t-
C1-C4 alkyl such as butyl or another organic group selected from groups known to undergo mild enzymatic or chemical hydrolysis when attached to the carboxylate moiety, such as trichloroethyl or A p-nitrobenzyl group is preferred. When M is a heavy metal M1 of +1 oxidation level, it is preferably Ag and in the compound of formula (I) n represents 1.

If M is a heavy metal M1 with +2 oxidation level, it is Hg
Preferably SCu or pbl[and n represents 2. When M is a group M2A, M2 preferably represents the above-mentioned +2 oxidized heavy metal M1, A is preferably an acetoxy or methoxycarbonyl group, more preferably a phenyl group υ, and n is 1
represents. A particularly preferred substituted alkyl group which R1 or R2 can represent is 1-hydroxyethyl, s, b
, the hydroxyl being a silyl ether, e.g. 1-
Preferably it is protected as t-butyldimethylsilyloxyethyl or as a carbonate such as 1-trichloroethoxycarbonyloxyethyl. More preferably R2 represents such a 1-hydroxyethyl group and R1 is hydrogen or R1 is hydroxyethyl and R2 is bromo. Particularly preferred R3 groups are methyl, trichloroethyl, p-nitrobenzyl, acetoxymethyl. A particularly preferred heavy metal M1 at +1 oxidation level is Ag, and a particularly preferred heavy metal M1 at +2 level is Hg. Many heavy metal salts of 04-mercaptoazetidinones are already known in the literature. R,L
Liebigs Ann, Ch by attre11
em, 1974.1957, Tetrahedron Lett by Mr. A Longo et al., 22+355
(1981), Can, J by Amarte et al.
, Chem. .

60.942 (1982), Tetrahedron Lett by F. DiNinno et al., 23,
3535 (1982), W.

Tetrahedron by T. Leanza et al.
Lett, 39.

2505 (1983), V.M., GiriJava
Tetrahedron L by Mr. llabhan et al.
ett, 24, 3179 (1983), VoM,
J by Girijavallabhan et al.
'Chem.

3oc, and Chem, Commun, 90
8 (1983).

The usefulness of the compounds of formula (II) as intermediates in the field of β-lactam antibiotics is obvious and partially demonstrated in the literature cited above. Indeed, these salts can be easily alkylated, acylated and converted into a large number of 4-azetidinylthio derivatives according to reactions known per se in the art. These derivatives can then be further manipulated on azetidinone N-adducts to give monocyclic β-lactam antibiotics such as monobactams or bicyclic β-lactam antibiotics such as nemes and cephems.

Direct synthesis of compounds of formula (I) has heretofore been needed and is now provided by the present invention. Indeed, the methods mentioned above and known in the art usually utilize azetidinyl) IJ tylsulfide or azetidinyl tetrahydropyranyl sulfide, either by total synthesis or via a multistep process from natural flycilins. must be synthesized.

Instead, the present invention makes it possible to directly convert flycilins to compounds of formula (I) under mild, non-critical conditions. Furthermore, the product of formula (I) does not need to be isolated and can be further converted into a closer precursor of the target compound in the reaction system.

According to the present invention, the formula (
The solution of starting honeycillin in II) is treated with a strong, poorly nucleophic base to render it nucleophilic.
ilicbase) and heavy metal M1 or M2A aggregate (ag-aggregate) (where Ml, M2
and A has the above definition). A preferred base is diazabicyclononene (1
), 1.4-u azabicyclooctane (DABCO) and diazabicycloundecene (DBU), preferred solvents are acetonitrile, dimethylformamide, benzene, dichloromethane, preferred heavy metal salts are silver nitrate, perchloric acid Silver, silver acetate, mercury acetate(ff), methoxycarbonylmercury(II) 7acetate and phenylmercury(II) chloride. The highest yield is generally 17
Temperatures ranging from 0'C to +100C are obtained; in some cases it is convenient to carry out the reaction at room temperature from 15 to 20C. An inert atmosphere and dry solvents are usually advantageous for protection from light. If it is desired to isolate the product, this can usually be carried out by an aqueous work-up, and the compound of formula (I) is usually extracted with standard organic solvents (eg ethyl acetate, dichloromethane). Alternatively, the heavy metal thiolates may conveniently be acylated or alkylated in the reaction system, more preferably acylated.

Alkylation of heavy metal mercaptides of formula (I) can be carried out using reactive halides such as methyl iodide, allyl bromide, benzyl bromide, and the like. α- of the formula (IN) where Haj is bromo or chloro, C1R4 is hydrogen or lower alkyl, especially methyl, X is oxygen, sulfur or a bond, and R5 is an organic group Alkylation with haloacyl derivatives gives azetidinyl derivatives of the following formula (IV), in which R1 to R5 and (e.g. J, Cbem, Soc, C'hem, by J, H, C, & yler et al.
C'ommun,', 1'973. 'I want to be). The object of the present invention is the acylation of heavy metal-mercaptides represented by formula (I), which are of the formula R6C0Y (where Y
is a chlorine atom, 0COR6, ocoR4' or an imidazolyl group, R6 is an organic group, and R6/ is R
This can be achieved within 2.3 minutes by the simple addition of an acylating agent (which is an organic group different from 6). Preferably, Y is a chlorine atom (1) and methyl or t-butyl is a phenylsilyloxymethyl group.

The resulting product has the following formula (V) (wherein R1, R2, R5, and R6 have the above definitions)
It is aze, tidinyl thioester represented by

The importance of azetidinyl thioesters in the synthesis of hardworms is well known (e.g. 1.
mi, 5try and Biology of β-L
actam Anti-biotica, 1982
, vol 2. Several routes to these intermediates from inams have been invented (see, pp. 315-559), but they are all associated with major drawbacks (M.

Tetrahedro by Mr. Alpegiani' et al.
n Lett, 1983°1638.1627). On the contrary, one according to the present invention is derived from Nam,
The preparation of azetidinyl thioesters of formula (V) is a simple, high-yielding, stereoselective process utilizing acyl chlorides of formula p, 6cocz, which are convenient reagents and often commercially available compounds. -It is a bot method.

In a mere three-step process, the formula (II) is a particularly convenient method for inducing the synthesis of a nem compound of formula (raccoon) from a nem compound of formula (raccoon) for the first time, which is described in detail in the present invention. This is an explanation.

02R5 (Vll) (Vl) In step (a), the benam compound of formula (It) is converted to the azetidinyl thioester of formula (V) as described above. Step (b), conversion of the compound of formula (V) to trial;xyphosphorane of formula (P/), is carried out using E.

Tetrahedron L by Perrone et al.
ett, 1984.

2399, followed by quenching of the osinide with excess trialkylphosphite) P(OR7)3, where R7 is a lower alkyl group, preferably ethyl or methyl. It is easily achieved.

The intermediate of formula (Vl) is then simply heated to obtain the desired penem of formula (■).

Example 1 Silver 3,3-dibromo-2-oxo-1-(trichloroethoxycarbonyl-2-methylpro-1-enyl)-
(4R)-acetidinyl thiolate, trichloroether in acetonitrile (12at)6.
6-dibromobonisilanate (1,011iS2.04
A solution of nitric acid, silver (0.4 IQ, 2.4 mmol) and diazabicyclononene (0.29 M, 2.4 mmol) was stirred at room temperature under an argon atmosphere. After 3 hours all starting material was converted to the title silver salt (by TLC monitoring).

Its isolation was carried out by partitioning between ethyl acetate and water. The organics were dried (MgSO4), the solvent was removed and the residue was triturated in isopropyl ether to give a powder (700 my). Melting point 160° (decomposed).

IR=νmax(xBr) 1790.1750 am
−'Kabuto=δ(CD(J3) 2.10 and 2.40
(3H, 8, Me, respectively), 4.90 (2H, ABq
, J=12Hz, CH2 people 6.15 (IH, a, 4-H
)ppm.

MS (FD) = 593 rV'z.

Silver 3,3-dibromo-1-(p-nitrobenzyloxycarbonyl-2-methylprop-1 -enyl)-2-okine-(4R)-azetidinyl thiolate was obtained as a fine yellow powder.

Melting point 115-120C (decomposed).

IR=j'max(KBr) 1790.1725
as-' average = δ (CDCJ5) 2fJ5 and 2u
5 (3H, s, Me, respectively), 5.25 (2H, m
, CH2), 5.87 (IH, s, 4-H), 7
．． 5 and 8.15 (2H, d, 8.5Hz respectively
, Ar) ppm Example 2 (4R)-Acetylthio-3,3-dibromo-1-(trichloroethoxycarbonyl-2-methylprop-1-
trichloroethyl 6.6-enyl)acetidin-2-one in acetonitrile (15a) under an argon atmosphere.
A solution of dibromopenicillate (1jl) was dissolved in silver nitrate (4jl).
16ju) and diazabicyclononene (292μl)
Processed with. After 3 hours at room temperature, acetyl chloride (174 μl) was added. A white precipitate of AgCl appeared immediately. After 10 minutes the reaction mixture was filtered and poured into ethyl ether-2% aqueous NaHCO3. The organic layer was dried and evaporated to give the crude title compound in quantitative yield. This material could be purified by silica gel chromatography. 0.89g (82%), melting point 8
7℃.

IR-=νmax(KBr) 1795.1745.1
720 amNMR=δ(cDc'15) 2. os,
2.39. 2.45 (5H, s each.

Me), 4.88 (2H,s, CH2CCA!5),
6.40(IH,S,4-H)99m MS(FD) = 529 m/z By following the same procedure as above, but when p-nitrobenzyl 6*6-'' bromo starts from nisyranate White powder (4R)-acetylthio-3,3-
Dibromo-1-(p-nitrobenzyloxycarbonyl-2-methylprop-2-enyl)azetidin-2-one, melting point 110-112°C.

I'R'=Sim,! 1x(KBr) 1790.172
0.17070s-'Nagiyama=δ(CD(J5) 2.0
．． 1231, 2.43 (3H, s, respectively
Me), 5.4 (2H,s,0CH2Ar), 6.1
5(IH,s,4-H')S7.55 and 8.23(
2H, a, r=a, sHz, Ar)])pm, respectively
is obtained, starting from methyl 6,6-dibromopenicylate, syrupy (4R)-7cetylthio 3,3-dibromo-1-(methoxycarbonyl-2-
Methylprop-1-enyl)azetidin-2-one, Ht = umax(CHCA'5) 1790.17
25.1710 sh, ors-'Nagigo=δ(CDCI
t3) 1.98. 2.30. 2.45 (3H, s each.

MgX2.83(3H,a,OMe), 6.22(I
H, s, 4-H) ppm was obtained, and t-butyl 6.6-
When starting from dibromopenicillanate, a white powder of (4R)-acetylthio-3,3-dibromo-1-(
t-Butoxycarbonyl-2-methylprop-1-enyl)azetidin-2-one, m, p, 18[]°C (decomposition) IR=νmax (KBr) 17B5.1710 br
(IB-'NMR=δ(CD(J'5) 1.55(
9H, S, C4H9), 1.95.2.27°2.43
(5H, S, Me, respectively), 6.30 (IH, s,
4-H) ppm was obtained, and trichloroethyl 6α
When starting from -bromo-6β-((IR)-t-butyldimethylsilyloxyethyl]penicylanate, (4R)-acetylthio-(3S)-bromo (38)
-((jR)-t-butyldimethylsilyloxyethyl)-1-(trichloroethoxycarbonyl-2-)fprop-1-enyl)azetidin-2-one, IR=νm&x(cHcl!,) 1780.1730
．． 1700cvi-'NMR=δ(CDIJ5) 0.
15. 0.16 (3H,s, SiMe2, respectively).

0.91 (9H, J3.C4H9), 1.51 (3
H, d, J=6Hz, CJ・CH')S2.02.2.
50. 2.36 (3H, s, Me, respectively).

4.83(2H,s, CH2CCJ5″)X6.10(
IH, s, 4-H) ppm was obtained.

Example 3 (4R)-t-Butyldiphenylsilyloxyacetylthio-3,3-dibromo-1-()IJdichlorotoxycarbonyl-2-methylprop-1-enyl)azetidin-2-one in dry benzene (25jlj) A solution of t-butyldiphenylsilyloxyacetic acid (1,5i) and thionyl chloride (0,72m) was kept at 25°C for 24 hours.

The reaction mixture was completely evaporated and excess reagents and volatile by-products were removed. In a separate container, trichloroethyl 6,6-dibromo in acetonitrile (12→
o, 5s4ar). After stirring for 6 hours at room temperature, a solution of the above acyl chloride in dry acetonitrile (101 ag) was added dropwise into it under stirring and soon a white precipitate of silver chloride appeared. After an additional 15 minutes the reaction mixture was washed and partitioned between water and ethyl acetate. The organic layer was washed with water, dried and evaporated to give a syrup which was purified by flash chromatography. 2. ! M (78chi).

IR=νmax 1795. j740.1710t
s-1aMR=δ(CDCIt5) 1.06(9H,
S, C4H9) S2.0(]$' and 2.32 (3H, s, Me, respectively), 4.25 (2H, s, 0CH
2CO), 4.80 (2H,s, 0CH2CC15χ
6.30 (IH, s, H-4χZ2~7.8 (10H,
m, Ar) ppm Example 4 (38)-((IR)-t-butyldimethylsilyloxyethyl1)-(4R)-t-butyldiphenylsilyloxyacetylthio-1-(1-trichloroethoxycarbonyl-2 -Methylprop-1-enyl)azetidin-2-one By following the experimental procedure described in Example 3, MeC
A solution of trichloroethyl 6α[(IR)-t-butyldimethylsilyloxyethyl]hodisilinate in N was reacted with silver nitrate and diazabicyclononene (1 molar equivalent each, 48 h, OC1 in the dark, N2) and then reacted. The mixture was treated with t-butyldiphenylsilyloxyacetyl chloride (1.1 molar equivalent, IH, 20°C) to give the title product (55% after silica gel chromatography).

IR=νmax(CHCJ3) 1760.1725.
1695 cm-'NMR= (200MHz, C
DC/5) δ0.07. 0.10 (3 each
H, S), 0.87. 1.06 (9H, s each
), 1.32 (3H, d, J=6.3Hz)
, 2.03, 2.26 (respectively 3H, s included 3.35 (IH.

d d , J = 2.6 and 6.7 Hz), 4.19
(2H, sχ 4.33 (IH.

dq, J=6.7 and 6.3Hz), 4.47.
4.85 (2H, respectively d, J=12.0Hzχ
5.76 (I H, d, J=2.6Hz or 7
．． 3-7.8 (IOH, m) Example 5 (4R)-7cetylthio(3S)-((IR)-t-
butyldimethylsilyloxyethyl)-1-(1-trichloroethoxycarbonyl-2-methylprop-1-dynyl)7zetidin-2-one acetonitrile (15aJ
) in trichloroethyl 6α-((IR)-t-butyldimethylsilyloxyethyl]beniciline) (45
A solution of phenylmercuric chloride (31
31m51,1 mmol) and azabicyclononene (
0.119au, 0.95 mmol). After stirring at room temperature for 2 hours, acetyl chloride (0.2 m
) was added and the mixture was stirred for an additional hour and then partitioned between ethyl acetate and water. The organic layer was sequentially treated with 4% HCI.
.

Washed with saturated NaHCO3, N20 and dried (Na2
804) and then evaporated. The residue was dissolved in CCl4 (1
The insoluble salts were removed and the solution was evaporated to give the title product in near quantitative yield.

IR = νma engineering (CH (J5) 1760.1725.
1695 cIrlNMR = (60MHz, CD
Cl3)δ0.10(6H,s')So,90(9
H, s), 1.30 (3H, d, J=6.2Hz),
2.03. 2.27. 2.32 (each A
H, s), 3.23 (IH, dd, J = 2.5 and 6
．． 5Hz),.

4.30 (IH, m), 4.80 (2H, sχ5.7
2 (I H, d, J = 25Hz) Mass spectrum = 531 (M"), 475 (M" -5
6, reference peak) Example 6 (4R)-7cetylthio(3R)-((IR)-t-
butyldimethylsilyloxyethyl)-1-(1-)
! J dichloroethyl 6β-((IR)-t-butyldimethylsilyl) by following the experimental procedure described in Example 5. Starting from oxyethyl]honisilynate, the title product was obtained in quantitative yield.

IR=νmax(CHC13) 1760.1730.
1690 os-'NMR= (200MHz, CDC
J3) δ0.09. 0.13 (3HIS each
), 0.87 (9H, s), t59 (5H, d, J
=6.4Hz), 1-98.2.21.

2.28 (3H+s and !1.58 (IH)
, dd, J==2.9 and 5.7Hz') S4.10
(IH, qd, J=2.9 and 6.4Hzχ 4.7
6゜4.84 (2H, each d, J=12DHZ
), 5.93 (1a, a,, b5.7Hz)

Claims (1)

[Claims] 1) The following formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R_1 and R_2 are each independently hydrogen, halogen, or an organic group, and R_3 is hydrogen or an organic group) in an aprotic organic solvent at a temperature of -700 to 100°C, a strong base and a heavy metal M_1 or M_2A aggregate (where M_1 is +1 or +2 oxidation state represents the heavy metals of
M_2 is a heavy metal in the +2 oxidation state and A is an organic or inorganic group). ) in which R_1, R_2 and R_3 have the abovementioned definitions, n is 1 or 2 and M represents a heavy metal M_1 or a group M_2A with the abovementioned definitions. 2) The strong base with poor nucleophilicity is diazabicyclononene,
2. The method of claim 1, wherein 1,4-diazabicyclooctane and diazabicycloundecene are selected. 6) The method according to claim 1, wherein the organic or inorganic salt of the heavy metal M_1 is silver nitrate, silver perchlorate, silver acetate or mercury acetate. 4) The method according to claim 1, wherein the organic salt of the M_2A aggregate is methoxycarbonylmercury(II) acetate or phenylmercury(II) chloride. 5) The method of claim 1, wherein the aprotic organic solvent is acetonitrile, dimethylformamide, benzene or dichloromethane. 6) The method of claim 1, wherein the reaction is carried out at 15-25°C. 7) In the formula, R_1 and R_2 are each independently bromine, a hydrogen atom or a protected 1-hydroxyethyl group, and R_3 is methyl, t-butyl, trichloroethyl or p-nitrobenzyl group, Range 1
Section method. 8) Compounds of formula I are represented by the formula R_6COY (where Y represents a chlorine atom, OCOR_6, OCOR_6' or an imidazolyl group, R_6 represents an organic group and R_6' is an organic group different from R_6) Acylated with a compound represented by the following formula ▲ mathematical formula, chemical formula, table, etc. ▼ (wherein R_1, R_2 and R_3 have the definitions given in Section 1 above and R_6 has the definition given above) A method according to claim 1 for obtaining an azetidinyl thioester. 9) The method according to claim 8, wherein Y represents a chlorine atom and R_6 is a methyl or t-butyldiphenylsilyloxymethyl group.